Tailoring modifications of polysaccharides in Mycobacterium tuberculosis

结核分枝杆菌多糖的剪裁修饰

基本信息

批准号：
10685409
负责人：
Mercedes Gonzalez-Juarrero
金额：
$ 63.76万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685409
关键词：
Academia Affect Amino Acids Anabolism Attention Bacillus Biochemical Biochemistry Biocide Biological Biological Markers C3HeB/FeJ Mouse COVID-19 Carbohydrate Chemistry Carbohydrates Cause of Death Cell Wall Cell surface Cells Charge Colorado Dendritic Cells Development Ensure Environment Exclusion Galactosamine Generations Genetic Genus Mycobacterium Glycobiology Gram-Positive Bacteria Granuloma Host Defense Infection Infectious Agent Knock-out Knowledge Laboratories Lipopolysaccharides Lung infections Macrophage Mediating Membrane Modeling Modification Mus Mycobacterium Infections Mycobacterium tuberculosis Natural Immunity Necrosis Pathogenesis Pathogenicity Pathology Patients Persons Physiological Physiological Processes Physiology Play Polysaccharides Prokaryotic Cells Research Personnel Resistance Role Stress Structure Surface Properties Taiwan Teichoic Acids Testing Therapeutic Universities Virulence Wheat acyl group adaptive immunity arabinogalactan cell envelope design environmental stressor immunopathology innovation inorganic phosphate lipoarabinomannan lipomannan microorganism multidisciplinary mutant mycobacterial pathogen physical property prophylactic response sugar thiosugar transcriptomics

项目摘要

Abstract The covalent modification of prokaryotic cell envelope glycans, namely lipopolysaccharide (LPS) and (lipo)teichoic acids, with discrete substituents such as sugars, amino acids, phosphates or acyl groups, is a well-known strategy used by Gram-negative and Gram-positive bacteria to modulate their cell surface properties, the way they interact with their environment, their resistance to biocides and host defenses, and pathogenicity. Although evidence exists that Mycobacterium tuberculosis (Mtb) similarly decorates its major cell envelope glycans, arabinogalactan (AG) and lipoarabinomannan (LAM), with various tailoring substituents, little is known of their biological significance. The discovery by our laboratories of the biosynthetic machineries responsible for the synthesis and transfer of these discrete motifs to AG and LAM, and the generation of the first Mtb knock-out mutants deficient in their biosynthesis have opened the way to studies aimed at understanding the function of these motifs in the physiology and immunopathogenesis of Mtb. We hypothesize that Mtb has evolved to modify its cell-envelope glycans with a distinct array of strategically placed substituents to promote its survival in the host environment. Accordingly, a multidisciplinary team of investigators with complementary expertise in mycobacterial cell envelope genetics and glycobiology, TB immunopathogenesis, and carbohydrate chemistry here proposes to investigate how simple (amino/thio)sugars or other charged groups strategically placed within the Mtb cell envelope landscape affect not only the physiology of this microorganism (Aim 1), but also the course of pulmonary infection, pathology and development of innate and adaptive immunity in infected C3HeB/FeJ mice (Aim 2), and the interactions of Mtb with host macrophages and dendritic cells thereby promoting survival within the host (Aim 3). Ultimately, these studies are expected to lead to significant new knowledge about the biological significance of understudied aspects of the unique cell wall of mycobacteria.

抽象的原核细胞包膜聚糖的共价修饰，即脂多糖（LPS）和 (脂)磷壁酸，具有独立的取代基，如糖、氨基酸、磷酸盐或酰基，是一种革兰氏阴性和革兰氏阳性细菌用来调节其细胞表面的众所周知的策略特性、它们与环境相互作用的方式、对杀菌剂和宿主防御的抵抗力，以及致病性。尽管有证据表明结核分枝杆菌 (Mtb) 类似地装饰了其主要细胞膜聚糖、阿拉伯半乳聚糖 (AG) 和脂阿拉伯甘露聚糖 (LAM)，具有各种定制取代基，人们对它们的生物学意义知之甚少。我们实验室发现的生物合成机器负责这些离散基序的合成和转移到 AG 和 LAM，以及生成第一个生物合成缺陷的 Mtb 敲除突变体为针对以下疾病的研究开辟了道路了解这些基序在结核分枝杆菌生理学和免疫发病机制中的功能。我们假设 Mtb 已经进化到用一系列独特的多糖修饰其细胞包膜聚糖战略性放置取代基以促进其在宿主环境中的生存。因此，一个多学科研究人员团队在分枝杆菌细胞包膜遗传学方面具有互补的专业知识糖生物学、结核病免疫发病机制和碳水化合物化学在这里建议研究如何简单的（氨基/硫代）糖或其他带电基团战略性地放置在 Mtb 细胞包膜景观中不仅影响这种微生物的生理学（目标1），而且影响肺部感染的过程，受感染的 C3HeB/FeJ 小鼠的先天性和适应性免疫的病理学和发育（目标 2），以及 Mtb 与宿主巨噬细胞和树突状细胞相互作用，从而促进宿主内的存活（目标 3）。最终，这些研究预计将带来关于生物学意义的重要新知识分枝杆菌独特细胞壁的待研究方面。